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Purpose of the article: The aim of this multicenter observational study is to report data from real world on the use of bimekizumab in patients aged ≥ 65 years with moderate-to-severe plaque psoriasis. Elderly patients are poorly represented in clinical trials on bimekizumab for plaque psoriasis, and real-world studies are important to guide clinical choices.Materials and methods: A retrospective multicenter study was conducted in 33 dermatological outpatient clinics in Italy. Patients aged ≥ 65 years, with moderate-to-severe plaque psoriasis and treated with bimekizumab were enrolled. No exclusion criteria were applied. Bimekizumab was administered following the Italian Guidelines for the management of plaque psoriasis and according to the summary of product characteristics, in adult patients who were candidates for systemic treatments. Overall, 98 subjects were included, and received bimekizumab up to week 36. Clinical and demographic data were collected before the initiation of treatment with bimekizumab. At baseline and each dermatological examination (4, 16, and 36 weeks), clinical outcomes were measured by the following parameters: (1) PASI score; (2) site-specific (scalp, palmoplantar, genital, nail) Psoriasis Global Assessment (PGA). At each visit, the occurrence of any adverse events (AEs) was recorded, including serious AEs and AEs leading to bimekizumab discontinuation.Results: The mean PASI score was 16.6 ± 9.4 at baseline and significantly decreased to 4.3 ± 5.2 after 4 weeks (p

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

BackgroundTherapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative G0 state, which is difficult to capture and whose mutational drivers remain largely unknown.ResultsWe develop methodology to robustly identify this state from transcriptomic signals and characterise its prevalence and genomic constraints in solid primary tumours. We show that G0 arrest preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We employ machine learning to uncover novel genomic dependencies of this process and validate the role of the centrosomal gene CEP89 as a modulator of proliferation and G0 arrest capacity. Lastly, we demonstrate that G0 arrest underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single-cell data.ConclusionsWe propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state.

In recent years, many countries have introduced Computational Thinking (CT) concepts into compulsory education as part of general curriculum reform efforts. A systematic review of academic and grey literature has been conducted to analyse the state of the art in implementing CT in primary and secondary education. In total, 1977 publications were identified, out of which 98 met the inclusion criteria for the review. The results show that, despite a lack of consensus on a common definition, a core set of key CT skills is addressed in primary and lower secondary education. Implementation approaches that emerged from the analysis are discussed and presented according to the European Commission's Joint Research Centre (2016) classification: (i) embedding CT across the curriculum as a transversal theme/skill set; (ii) integrating CT as a separate subject; and (iii) incorporating CT skills within other subjects such as Mathematics and Technology. New approaches to formative assessment of CT are emerging, reflecting different conceptualisations and differences in contextual and motivational aspects of CT curriculum integration. However, further investigation is needed to understand better how gender/equity/inclusion issues impact the quality of computing education integration.

MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 × 10-6). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB-controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31-associated EGLN3/NF-κB-controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31-/- rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development.

Attention is an important, multifaceted cognitive domain that includes many key cognitive processes involved in learning. This study aimed to identify the predictive links between different components of attentional skills and core calculation skills development, using two standardized measures assessing calculation (AC-MT 6-11) and attention skills (CAS) in a sample of 143 typically developing children of age range from 7.6 years to 9.4 years. The results showed that in 2nd grade, selective visuo-spatial attention emerged as an important predictor in the written calculation task, while the ability to inhibit distracting information seemed to better predict accuracy in oral calculation. In 3rd grade, visuo-spatial components of attention emerged as no longer predictive, whereas planning and active visuo-spatial attention abilities emerged as predictive of accuracy in the oral calculation task. These results confirm previous findings about the contribution that attentional skills may have in calculation skills development, supporting evidence for progressive automation attentional components over time.

Abstract Background Several studies have attempted to characterise the origin of canine transmissible venereal tumour (CTVT). However, the participation of cancer stem cells (CSC) has not been reported Objectives Herein we describe the expression patterns of CSC markers CD44, CD34, CD90 and CD133 in CTVT Methods Thirty‐eight samples were selected and assessed through flow cytometry and immunohistochemistry Results and conclusions Twenty‐two tumours were classified as plasmacytoid and 16 as mixed. Almost all tumours showed high CD44 and low CD34 levels. CD133 and CD90 expression varied among tumours. Cytological groups did not differ in the proportion of CSC markers. Our results suggest that CSC subpopulations might participate in CTVT.

Abstract The present work aims at the application of different optimization strategies in the electromagnetic analysis of the Variable Reluctance Motor (VRM) through Finite Element (FE) simulation. Two case studies are investigated: the first one aims to optimize the geometry and electrical characteristics of windings of a single-phase VRM 6/6, minimizing copper losses; the second aims to optimize a restricted set of geometric parameters of a 4- phase VRM 8/6, maximizing the flux linkage in the phase coils per unit volume of magnetic core. In this way, by using the Finite Element Method (FEM), the results from the Differential Evolution (DE) and Particle Swarm Optimization (PSO) algorithms will be compared and highlighted. Then, the magnetic flux densities of the motors are analyzed before and after the optimization. The results obtained show good efficiency of the algorithms, since the objective functions were satisfied with respect to the reference models.

Abstract Background There is a need for new approaches in agriculture to improve safety of final products as well as to increase environmental acceptability. In this paper, the biodynamic preparation 501 (horn silica) was sprayed on Vitis vinifera (L.) cv Garganega plants in two vineyards located in Veneto region, North-East Italy. Leaf samples were collected on the day of 501-treatment and 11 days later, and berries were sampled at harvest time. Leaves and berries samples were analysed combining targeted and untargeted measurements related to primary metabolism (pigment, element and amino acid contents) and to secondary metabolism. Chlorophyll content in leaves, and amino acid and element (C, N, S) analysis in berries were combined with untargeted UPLC-QTOF metabolomics. Results The discriminant compounds related to the 501-treatment were annotated on the basis of accurate MS and fragmentation and were identified as secondary metabolites, namely phenolic constituents belonging to the shikimate pathway. The level of most of the identified compounds increased in plants treated with 501 preparation. Conclusions Results highlight the prominent value of the metabolomic approach to elucidate the role of the 501 applications on grapevine secondary metabolism. Graphical Abstract

BackgroundAlthough studies have consistently found an association between childhood leukaemia risk and magnetic fields, the associations between childhood leukaemia and distance to overhead power lines have been inconsistent. We pooled data from multiple studies to assess the association with distance and evaluate whether it is due to magnetic fields or other factors associated with distance from lines.MethodsWe present a pooled analysis combining individual-level data (29,049 cases and 68,231 controls) from 11 record-based studies.ResultsThere was no material association between childhood leukaemia and distance to nearest overhead power line of any voltage. Among children living

Abstract The constant growth of distributed energy resource (DER) in the electric power system (EPS) is a reality on account of some aspects, for example, technical, financial, environmental. The insertion of DERs can be positive, providing ancillary services, for example, harmonic mitigation, or negative, causing overvoltage, depending on the proper control and the characteristics of the grid. This paper proposes a pq‐based control strategy for distributed generation, wherein the studied system is composed by a photovoltaic DER and a three‐phase converter for processing the generated power and providing ancillary services (ASs) to a three‐wire EPS. The power control is based on the power balance between the grid and the converter. Besides supplying active and reactive power, the proposed strategy can provide ASs by controlling the grid currents from a pq transformation. Some advantages over other solution can be mentioned, such as reduced sensor number and instantaneous control response. In addition, neither additional harmonic‐extraction method nor a phase‐locked loop is required. To validate this study and theoretical considerations, simulation results are presented and evaluated. From tests in a downscaled laboratory setup, experimental results are also presented to verify the effectiveness of the proposed control strategy.

itor Title: Varicella zoster virus reactivation antedating ipsilateral brainstem stroke Authors: Giuliana Galassi1, Maurilio Genovese2, Marisa Meacci3, Marcella Malagoli2 Affiliations: 1Department of Biomedical, Metabolic, Neural Sciences, University Hospital of Modena, Italy, 2Neuroradiology Service, University Hospital of Modena, Italy, 3Department of Laboratory Medicine and Patholgy, Microbiology and Virology Unit, University Hospital of Modena, Italy Corresponding Author: Giuliana Galassi, MD, Department of Biomedical, Metabolic, Neural Sciences, University Hospital of Modena, Via P. Giardini 1455, Modena, Italy, Tel: 39-3497325802, Email: giulianagalassi46@gmail.com Abstract: Varicella zoster virus (VZV) infection and reactivation are associated with a number of neurologic conditions. Unifocal large vessel infarcts may follow zoster in the trigeminal or cervical distribution as a result of transaxonal transport of virus from trigeminal or cervical afferent fibers that innervate vessels. Ophthalmic zoster (HZO) might cause ophthalmoplegic syndromes, with secondary optic neuritis. Mechanisms include local orbital muscle inflammation and, viral spread from the ophthalmic branch of the fifth nerve with associated vasculopathy. A 72-year-old man developed a vesicular rash in the territory of C5-T5-6. Within four weeks, the patient developed headache, dysphagia, left facial and extremity ataxic weakness. Magnetic resonance imaging (MRI) revealed a right pontine infarction. A 66-year-old woman presented with right-sided painfull HZO. One week later she developed complete external ophthalmoplegia and blurred vision. MRI showed ill-defined signal alteration in the retrobulbar tissue. Three weeks later, the patient was admitted because of dysarthria, deviated tongue, left-sided limb weakness, and tactile hypoesthesia. Spinal fluid contained 23 lymphocytes/mm3 and increased protein. The serum contained antibodies to VZV IgG and IgM in both cases. The patients received intravenously acyclovir with improvement. This report confirms unusual occurrence of ipsilateral brainstem stroke after VZV reactivation in immunocompetent subjects.

Abstract Background Psoriasis is a chronic immune-mediated inflammatory skin disease which can also involve joints. It is often associated with burdensome comorbidities which negatively impact prognosis and quality of life (QoL). Biologic agents have been shown to be effective in controlling disease progression, but their use is associated with higher costs compared with traditional systemic treatments. The economic analysis of the CANOVA (EffeCtiveness of biologic treAtmeNts for plaque psOriasis in Italy: an obserVAtional longitudinal study of real-life clinical practice) study aims to assess the costs and cost-effectiveness of biologics in a real-world context in Italy. Methods The annualised overall direct costs of moderate-to-severe plaque psoriasis management, the annualised cost of biologic drugs and the cost per responder in the Italian National Health System perspective were assessed. More specifically, the cost per response and cost per sustained response of the most prescribed biologic therapies for the treatment of moderate-to-severe plaque psoriasis within the CANOVA study were assessed using the Psoriasis Area Severity Index (PASI) at several score levels (75, 90 and 100%). Results The most frequently used biologic therapies for plaque psoriasis were secukinumab, ustekinumab, adalimumab originator, and ixekizumab. Cost of biologics was the driver of expenditure, accounting for about 98% of total costs. Adalimumab originator was the biologic with the lowest cost per responder ratio (range: €7848 - €31,378), followed by secukinumab (range: €9015 - €33,419). Ustekinumab (range: €11,689 – €39,280) and ixekizumab (range: €11,092 – €34,289) ranked respectively third and fourth, in terms of cost-effectiveness ratio. As concerns the cost per sustained response analysis, secukinumab showed the lowest value observed (€21,375) over the other options, because of its high response rate (86% vs. 60–80%), which was achieved early in time. Conclusion Biologic therapy is a valuable asset for the treatment of moderate-to-severe plaque psoriasis. Concomitant assessment of treatment costs against the expected therapeutic response over time can provide physicians and payers additional insights which can complement the traditional risk-benefit profile assessment and drive treatment decisions.

BackgroundFall risk in the elderly is a major public health issue due to the injury-related consequences and the risk of associated long-term disability. However, delivering preventive interventions in usual clinical practice still represents a challenge.AimTo evaluate the efficacy of a multiple-component combined with a multifactorial personalized intervention in reducing fall rates in a mixed population of community-dwelling elderly compared to usual care.DesignRandomized Controlled Trial (NCT03592420, clinicalTrials.gov).SettingOutpatients in two Italian centers.Population403 community-dwelling elderly at moderate-to-high fall risk, including subjects with Parkinson's Disease and stroke.MethodsAfter the randomization, the described interventions were administered to the intervention group (n = 203). The control group (n = 200) received usual care and recommendations to minimize fall risk factors. In addition, each participant received a fall diary, followed by 12 monthly phone calls. The primary endpoint was the total number of falls in each group over 12 months, while the secondary endpoints were other fall-related indicators recorded at one year. In addition, participants' functioning was assessed at baseline (T1) and 3-month (T3).Results690 falls were reported at 12 months, 48.8% in the intervention and 51.2% in the control group, with 1.66 (± 3.5) and 1.77 (± 3.2) mean falls per subject, respectively. Subjects with ≥ 1 fall and ≥2 falls were, respectively, 236 (58.6%) and 148 (36.7%). No statistically significant differences were observed between groups regarding the number of falls, the falling probability, and the time to the first fall. According to the subgroup analysis, no significant differences were reported. However, a statistically significant difference was found for the Mini-BESTest (p = 0.004) and the Fullerton Advanced Balance Scale (p = 0.006) for the intervention group, with a small effect size (Cohen's d 0.26 and 0.32, respectively), at T1 and T3 evaluations.ConclusionsThe intervention was ineffective in reducing the number of falls, the falling probability, and the time to the first fall at 12 months in a mixed population of community-dwelling elderly. A significant improvement for two balance indicators was recorded in the intervention group. Future studies are needed to explore different effects of the proposed interventions to reduce falls and consequences.

Introduction Diseases related to the lesions of upper or lower motor neurons, such as spina bifida, myopathy, and residual polio, often cause severe deformities of the foot and ankle. The treatment goal is to convert a deformed and rigid foot into a plantigrade foot. Matherial and method We treated 51 neurological feet from 2001 to 2018 with the Ilizarov method. They were polio outcomes in 27 cases, 17 feet were affected by spina bifida, 6 other patients had Charcot-Marie-Tooth disease. Results Results were assessed by comparing appearance and function before and after surgery described by Dimeglio, and modified by Dong Y.L. et al. Before surgery, there were 33 moderate and 28 severe deformities (average preoperative scores, 6.3). The mean time required to correct a deformity was 37.1 days (range, 22–58 days) and the mean time for stabilization was 67.2 days (range, 45–98 days). At latest follow-up (mean 7.42 years, from 13 month to 16 years), clinical outcomes and patient satisfaction were considered acceptable. 28 patients achieved an excellent outcome and 21 patients had a good outcome, two feet were classified as having a poor result. Nearly 86 % of patients (44 patients) were satisfied with their outcomes and replied they would repeat their procedure. Complications include infection in 15 % of K-wire tracts, Dysesthesia in 5 cases, superficial necrosis in 3. One patient developed knee contracture. 2 patients were re-operated with V osteotomy. Conclusions The Ilizarov method represents a great resource in the treatment of severe neurological deformities of the foot.

Abstract Since the discovery of high temperature superconductors, a possible cryogen-free scenario has always been wished. Nowadays, liquid Helium is running out, and it is likely that the cooling by will be a large part of the costs of any superconducting system. Bi-2212 wires at temperature higher than 4.2 K still show a very high irreversibility field and thus a deep investigation of their properties in such a range of temperature is very useful in order to assess the applicability in high field cryogen-free magnets. Here electrical transport and magnetic properties characterization at variable temperature and magnetic field on our “GDG—processed” wires are reported together with a well-described original approach to calculate the irreversibility field H irr. This study is devoted to provide reference data on the behaviour of the only isotropic wire for high field application with an eye to the performances at temperatures above 4.2 K.

Background: Match and notational analysis are well-recognised methods to collect important information about technical-tactical indicators in racket sports (shot, footwork, ball placement, and outcome). The purpose of this study was to analyse the principal indicators, with a special focus on comparing the playing style of women and men high-level players. Methods: twenty matches played by 40 women, and twenty matches played by 40 men were analysed in slow motion by an expert coach. All the players were in the top 111(W) and 120 (M) positions of the ITTF world ranking; Results: women play more shots/rallies and shots/games compared to men. The most used shots are Top forehand and Serve for both groups. Women also prefer to play backhand block and drive. Conversely, men prefer to counterattack with forehand Top C Top. One step is often used by women, and they also prefer to hit the ball without performing any step. Conversely, men perform crossover and pivot footwork. Serves are generally directed to close-to-the-net areas, and the following shots are typically directed to the backhand corner during the rallies. Conclusions: Women showed a specific distribution of technical indicators with respect to men players, suggesting sex-specific training sessions. [ABSTRACT FROM AUTHOR]

Abstract Background There is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients’ samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL. Methods We assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models. Results High FOXP3/CD3 ratios (p = 0.001), high IL17A levels (p = 0.003) and low IL2 levels (p = 0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p = 0.02). In the SNV model, the CC haplotype of IL10 (p

Abstract Insects entombed in copal, the sub-fossilized resin precursor of amber, represent a potential source of genetic data for extinct and extant, but endangered or elusive, species. Despite several studies demonstrated that it is not possible to recover endogenous DNA from insect inclusions, the preservation of biomolecules in fossilized resins samples is still under debate. In this study, we tested the possibility of obtaining endogenous ancient DNA (aDNA) molecules from insects preserved in copal, applying experimental protocols specifically designed for aDNA recovery. We were able to extract endogenous DNA molecules from one of the two samples analyzed, and to identify the taxonomic status of the specimen. Even if the sample was found well protected from external contaminants, the recovered DNA was low concentrated and extremely degraded, compared to the sample age. We conclude that it is possible to obtain genomic data from resin-entombed organisms, although we discourage aDNA analysis because of the destructive method of extraction protocols and the non-reproducibility of the results.

ImportanceThere is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure.MethodsA nationwide study involving 125 Italian Coronary Care Units recruited 2,000 patients between 1998 and 2002 hospitalized for a type I myocardial infarction before the age of 45 years (male, n = 1,778 (88.9%). Patients were followed up for a median of 19.9 years (IQR 18.1–22.6). The primary composite endpoint was the occurrence of cardiovascular death, non-fatal myocardial re-infarction or non-fatal stroke, and the secondary endpoint of hospitalization for revascularisation by means of a percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG).ResultsST-elevation MI was the most frequent presentation among both men and women (85.1 vs. 87.4%, p = ns), but the men had a greater baseline coronary atherosclerotic burden (median Duke Coronary Artery Disease Index: 48 vs. 23; median Syntax score 9 vs. 7; both p < 0.001). The primary composite endpoint occurred less frequently among women (25.7% vs. 37.0%; adjusted hazard ratio: 0.69, 95% CI 0.52–0.91; p = 0.01) despite being less likely to receive treatment with most secondary prevention medications during follow up.ConclusionsThere are significant sex-related differences in baseline risk factors and outcomes among patients with early-onset MI: women present with a lower atherosclerotic disease burden and, although they are less frequently prescribed secondary prevention measures, experience better long-term outcomes.Trial Registration4272/98 Ospedale Niguarda, Ca' Granda 03/09/1998.